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Experimental Biology and Medicine 231:1638-1645 (2006)
© 2006 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Kinetics of Cisplatin and Its Monohydrated Complex with Sulfur-Containing Compounds Designed for Local Otoprotective Administration

Pernilla Videhult*,{dagger},1, Göran Laurell{ddagger}, Inger Wallin* and Hans Ehrsson*,{dagger}

* Karolinska Pharmacy, Karolinska University Hospital, Stockholm, Sweden; {dagger} Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; and {ddagger} Institute for Hearing and Communications Research, Karolinska Institutet, Stockholm, Sweden

1 To whom requests for reprints should be addressed at Karolinska Pharmacy, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail: pernilla.videhult{at}apoteket.se


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
The anticancer drug cisplatin can cause permanent inner ear damage. We have determined the second-order degradation rate constant, kNu, of cisplatin and its more toxic monohydrated complex (MHC) in the presence of each of the sulfur-containing nucleophiles N-acetyl-L-cysteine, L-cysteine methyl ester, 1,3-dimethyl-2-thiourea, D-methionine, and thiosulfate, compounds that are under evaluation for local administration to prevent cisplatin-induced ototoxicity. MHC was isolated from a hydrolysis solution of cisplatin using liquid chromatography (LC). The degradations were evaluated by measuring the disappearance of MHC and cisplatin at 37°C and pH 7.4 in the presence of each of the nucleophiles using LC and photometric detection. The kNu of MHC and of cisplatin was 0.044 M–1sec–1 and 0.012 M–1sec–1 with N-acetyl-L-cysteine, 0.24 M–1sec–1 and 0.067 M–1sec–1 with L-cysteine methyl ester, 0.16 M–1sec–1 and 0.074 M–1sec–1 with 1,3-dimethyl-2-thiourea, 0.070 M–1sec–1 and 0.069 M–1sec–1 with D-methionine, and 3.9 M–1sec–1 and 0.091 M–1sec–1 with thiosulfate, respectively. Our results suggest that thiosulfate, as being the strongest nucleophile, is a promising candidate for local application in order to reduce the inner ear content of MHC and cisplatin. However, otoprotection is a multifactorial event, and it remains to be established how important nucleophilicity is for the effectiveness of the protecting agent.

Key Words: antioxidants • cis-diamminedichloroplatinum • hydrated species • nucleophiles • ototoxicity


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Cisplatin (Fig. 1aGo) holds a central position in the treatment of solid malignant tumors, such as testicular cancer, head and neck cancer, ovarian cancer, bladder cancer, and some pediatric malignancies. The monohydrated complex (MHC, Fig. 1bGo) is formed upon hydrolysis of cisplatin and is generally considered the key molecule in the antitumoral action of the drug (1). MHC is present in the blood from patients receiving cisplatin infusions, its area under the concentration-time curve (AUC) being approximately 15% of that of cisplatin (2). Inside the cell, the formation of MHC is more favored, since the concentration of chloride ions is lower (1).


Figure 1
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  		Figure 1. The molecular structures of the platinum and the sulfur-containing compounds used in the present study: cisplatin (a), the monohydrated cisplatin complex (MHC, b), N-acetyl-L-cysteine (c), L-cysteine methyl ester (d), 1,3-dimethyl-2-thiourea (e), D-methionine (f), and thiosulfate (g).

 
Though cisplatin has been used clinically since the 1970s, the molecular basis for its cytotoxicity is still not fully elucidated. Treatment with cisplatin leads to the formation of platinum-DNA adducts, which are usually considered fundamental for the antitumoral effect (1). However, platinum adducts are formed with many other essential biomolecules, especially those containing sulfur (3). It has also been shown that cisplatin is cytotoxic to enucleated cells, inducing apoptotic signaling (4).

Cisplatin therapy is associated with gastrointestinal toxicity, nephrotoxicity, and ototoxicity. Of these, inner ear damage is the only side effect without any treatment available today. The high incidence of cisplatin-induced ototoxicity is a major problem, and it is more pronounced in children (5).

For many years, sulfur-containing compounds, due to their high affinity for platinum molecules, have been attractive candidates for development of protecting agents against cisplatin-induced nephrotoxicity and ototoxicity. Many of these agents are antioxidants and radical scavengers. Since it has been discovered that cisplatin toxicity may be related to oxidative stress (4, 6), the sulfur-containing compounds might offer cytoprotection through their nucleophilic as well as antioxidating properties. Several of the compounds, for example N-acetyl-L-cysteine (7, 8), 1,3-dimethyl-2-thiourea (9), methionine (10–12), and thiosulfate (8, 13, 14), have decreased the toxicity in experimental animals when administered systemically in conjunction with cisplatin. Thiosulfate has also shown nephroprotective potential in humans (15). Unfortunately, the coadministration may also reduce the antineoplastic activity (8, 11–13). The reductions in effects and side effects are most likely caused by a decrease in the AUC of cisplatin and/or MHC (15, 16). If the antitumoral properties of cisplatin are to be conserved, a protector with a high affinity for platinum compounds should probably not be distributed to the cancer tissue. In vivo studies have revealed that local administration of a sulfur-containing compound to the middle ear for uptake to the inner ear may be a possible clinical approach for otoprotection (12, 17–19).

Several properties may be important for the effectiveness of a locally administered otoprotectant. In addition to being a nucleophile and an antioxidant, the otoprotectant must be able to pass from the middle ear cavity to the inner ear, possibly primarily via the round window membrane. This thin membrane separates the basal part of the scala tympani in the cochlea from the middle ear cavity and can act as a semipermeable membrane. Cellular uptake into the target cells for cisplatin toxicity as well as clearance from the inner ear compartments must also be taken into consideration. In the present study, we have explored the nucleophilicity of five sulfur-containing compounds under evaluation for local otoprotective administration by determining the degradation rate constants of MHC and of cisplatin in the presence of these nucleophiles. The nucleophiles studied are N-acetyl-L-cysteine, L-cysteine methyl ester, 1,3-dimethyl-2-thiourea, D-methionine, and thiosulfate (Fig. 1c–gGo). To the best of our knowledge, this is the first paper presenting degradation rates of isolated MHC.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Chemicals.
Cisplatin (Platinol 1 mg/ml, Bristol-Myers Squibb Company, New York, NY) was used in the degradation studies of cisplatin. Cisplatin (Sigma-Aldrich, St. Louis, MO) was used for preparation of MHC, similar to the method of Ehrsson et al. (20). In short, cisplatin was dissolved in water to a concentration of about 4 mM and was left to hydrolyze at room temperature for two days. Sodium hydroxide (1% v/v 1 M) was added to achieve the less reactive uncharged form of MHC (3). MHC was isolated with a porous graphitic carbon column (Hypercarb, 100 x 4.6 mm i.d., particle size 5 µm, Thermo Electron Corporation, Runcorn, UK) and a mobile phase of sodium hydroxide (0.5 mM). Detection was performed photometrically at 283 nm. For quantification, comparison was made with a reference solution containing 1.1 mM MHC as determined with atomic absorption spectroscopy performed by Analytica AB (Täby, Sweden). To minimize the conversion of MHC to the dihydrated cisplatin complex and its possible polymerization (21), all alkaline solutions containing isolated MHC were protected from light and stored on ice or, if not used within one day, at –80°C. Sodium thiosulfate and N-acetyl-L-cysteine were purchased from Merck (Darmstadt, Germany). D-methionine, L-cysteine methyl ester, and 1,3-dimethyl-2-thiourea were derived from Sigma-Aldrich. The water used was purified with a Milli-Q Water Purification System from Millipore Corporate (Billerica, MA). All other chemicals were of analytical grade, were obtained from commercial suppliers, and were used without further purification.

Apparatus.
The degradations of cisplatin and of MHC were evaluated by measuring their disappearance using an LC system consisting of a Valco Model C6W injector (Houston, TX) with a fixed loop volume of 20 µl for cisplatin and 5 µl for MHC, a LC-10ADvp pump, and a DGU-14A degasser, both devices from Shimadzu (Kyoto, Japan). MHC was analyzed with a Hypercarb column (150 x 3 mm i.d., particle size 3 µm, Thermo Electron Corporation) and quantified photometrically using microwave-assisted post-column derivatization with sodium N,N-diethyldithiocarbamate with an Initiator system from Biotage (Uppsala, Sweden), similar to the method of Ehrsson and Wallin (22), except that the mobile phase consisted of sodium hydroxide (1.0 mM). Cisplatin was analyzed with a self-packed strong anionic exchanger column (200 x 4.6 mm i.d.) of Nucleosil SB (particle size 5 µm, Macherey-Nagel, Düren, Germany) and a mobile phase of succinic acid (40% v/v 55 mM pH 5.0) and methanol (60% v/v), similar to the method described by Andersson and Ehrsson (23), except that no post-column derivatization was used. The UV absorbance was measured at 344 nm for MHC and 303 nm for cisplatin with a SPD-10AVvp UV-VIS detector (Shimadzu). The signal was plotted with a flatbed recorder (Kipp & Zonen, Delft, The Netherlands) and collected and processed with a Chromeleon integration system (version 6.20, Dionex Corporation, Sunnyvale, CA) for MHC and with a PC Integration Pack system (version 3.00, Kontron, München, Germany) for cisplatin.

Degradation of MHC.
The degradation of MHC in the presence of N-acetyl-L-cysteine, L-cysteine methyl ester, 1,3-dimethyl-2-thiourea, D-methionine, and sodium thiosulfate, respectively, was performed at 37°C in HEPES (10 mM), pH 7.4. A fresh solution of the nucleophile to be studied was prepared immediately before the incubation. The initial concentration of MHC was 30 µM, whereas that of the nucleophile ranged from 0.50 to 3.5 mM. All solutions were incubated in the dark in a thermostated water bath (Grant Instruments, Herts, UK) for at least four half-lives of the analyte. The pH was measured at the start and the end of the incubation. Samples were collected at appropriate intervals, quenched with ice-cold sodium hydroxide (25% v/v 0.1 M), and stored on ice for a maximum of 10 mins before freezing at –80°C. They were analyzed within 24 hrs.

Degradation of Cisplatin.
The degradation of cisplatin in the presence of the same nucleophiles as in the MHC experiments was performed at 37°C in HEPES (0.10 M), pH 7.4. A fresh solution of the nucleophile to be studied was prepared immediately before the incubation. The initial concentration of cisplatin was 0.20 mM, whereas that of the nucleophile ranged from 5.2 to 29 mM. The concentration of chloride ions was 8.7 mM and derived from Platinol. Most probably, this had no effect on the degradation rate, since the sulfur-containing compounds are much stronger nucleophiles than the chloride ion (24, 25). Solutions were incubated as in the MHC experiments, and the pH was measured at the start and the end of the incubation. Samples were collected at appropriate intervals and quenched on ice until analysis, which was performed the same day.

Data Analysis.
When the nucleophile is in large excess over the platinum compound, the substitution kinetics of square-planar Pt(II) compounds proceed by the general rate law for pseudo first-order kinetics


Formula 1(1)

where A is the concentration of the analyte at time t, Ao is the initial concentration of the analyte, and kobs is the pseudo first-order rate constant of the analyte. The pseudo first-order rate constant can be expressed by


Formula 2(2)

and is thus dependent on k1, which is the sum of the pseudo first-order rate constants for the reaction of the analyte with the solvent, for example HEPES and water; kNu, which is the second-order rate constant for the reaction of the analyte with a specific nucleophile; and [Nu], which is the concentration of that nucleophile (26).

The concentrations of MHC and of cisplatin, represented by their LC-UV peak areas, were plotted versus time. The curves were fitted to the equation of one phase exponential decay according to Equation 1. By determining kobs at a variety of different nucleophile concentrations, kobs can be plotted versus [Nu], and linear regression analysis will yield a straight line, with kNu being the slope and k1 the y-intercept (Equation 2). Slopes were compared using regression analysis. All calculations were performed using GraphPad Prism version 3.00 for Windows (GraphPad Software, San Diego, CA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
The disappearance of MHC and of cisplatin in the presence of the nucleophiles studied was followed using LC-UV, and representative chromatograms from different time points are given in Figures 2Go and 3Go. As expected, the decrease in analyte concentration proceeded according to Equation 1 and two representative plots are given in Figure 4Go.


Figure 2
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  		Figure 2. LC elution profiles of samples taken from a solution of MHC (initial concentration 30 µM) incubated with thiosulfate (1.4 mM) at pH 7.4 and 37°C for 0.3 (top), 3.6 (middle), and 10.3 mins (bottom). The peaks at approximately 7.5 and 10.2 mins represent the front and MHC, respectively. The two top chromatograms have been shifted up along the y axis. Column: porous graphitic carbon column (Hypercarb 150 x 3 mm i.d., particle size 3 mm). Mobile phase: 1.0 mM sodium hydroxide. Flow rate: 0.2 ml/min. Detection: photometrically at 344 nm after on-line microwave-assisted post-column derivatization with N,N-diethyldithiocarbamate (2.7 mM in methanol, flow rate 0.2 ml/min) at 115°C.

 

Figure 3
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  		Figure 3. LC elution profiles of samples taken from a solution of cisplatin (initial concentration 0.20 mM) incubated with thiosulfate (11 mM) at pH 7.4 and 37°C for 0.3 (top), 45 (middle), and 105 mins (bottom). The peaks at approximately 5 and 11 mins represent the front and cisplatin, respectively. The two top chromatograms have been shifted up along the y axis. Column: self-packed strong anionic exchanger column (200 x 4.6 mm i.d.) of Nucleosil SB (particle size 5 µm). Mobile phase: succinic acid (40% v/v 55 mM, pH 5.0) and methanol (60% v/v). Flow rate: 0.5 ml/min. Detection: photometrically at 303 nm.

 

Figure 4
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  		Figure 4. The time-dependent content of MHC (initial concentration 30 µM) and of cisplatin (initial concentration 0.20 mM) of samples taken from solutions containing thiosulfate (0.50 mM for MHC and 5.3 mM for cisplatin) at 37°C and pH 7.4. Each symbol represents one sample. Quantification was performed with liquid chromatography and photometric detection.

 
In the presence of thiosulfate, the MHC content decreased significantly more quickly than that of cisplatin (P < 0.0001), as illustrated in Figure 4Go. The linear regression analyses of kobs of MHC and of cisplatin versus the thiosulfate concentration can be seen in Figure 5Go. The kNu of MHC and of cisplatin with each of the nucleophiles studied is given in Table 1Go. The kNu of MHC was significantly larger than that of cisplatin in the presence of L-cysteine methyl ester (P = 0.0035) and 1,3-dimethyl-2-thiourea (P = 0.041), whereas it did not differ significantly in the presence of N-acetyl-L-cysteine (P = 0.061) or D-methionine (P = 0.99).


Figure 5
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  		Figure 5. The observed degradation rate constant, kobs, of MHC and of cisplatin versus the thiosulfate concentration at 37°C and pH 7.4. Each symbol represents one experiment. Bars represent 95% confidence interval.

 

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  		Table 1. The Degradation Rate Constants of MHC and of Cisplatin in Solutions with Sulfur-Containing Compounds at 37°C and pH 7.4a
 
The MHC content decreased rapidly in solutions with L-cysteine methyl ester and, in particular, with thiosulfate compared to the other nucleophiles studied. All P values are given in Table 2Go.


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  		Table 2. Comparison of the Second-Order Rate Constants of MHC and of Cisplatin, Which Are Given in Table 1Go, Using Linear Regression Analysis
 
Cisplatin was significantly more stable in solutions with N-acetyl-L-cysteine than with the other nucleophiles, as can be seen in Tables 1Go and 2Go. The kNu of cisplatin in the presence of the other nucleophiles was in the same range (Table 1Go), although some of them differed significantly (Table 2Go).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
When cisplatin is dissolved in water, the chloride ions are displaced by water molecules in a stepwise manner, leading to the formation of primarily MHC and a dihydrated complex (27). The hydrated species of cisplatin have been shown to be more toxic in vitro (28–32) and more nephrotoxic in vivo (29, 32–35) compared to cisplatin. Furthermore, MHC has been shown to be more ototoxic than cisplatin in vivo (34). Under physiological conditions, MHC is probably the only hydrated species present in considerable amounts (27, 36, 37). However, few studies have been performed on isolated MHC (16, 31, 34), even though it is readily obtainable using the method of Ehrsson et al. (20). In this paper, we present the rate constants for the disappearance of isolated MHC and of cisplatin when incubated with five sulfur-containing nucleophiles, which are under evaluation for local otoprotective administration. As expected, our results suggest MHC as being more reactive than cisplatin. MHC disappeared extremely quickly in the presence of thiosulfate (Table 1Go). This preferred reactivity can be due to the electrostatic attraction between the partially positively charged MHC and the doubly negatively charged thiosulfate.

A few studies have been published on the reactivity of the hydrated complexes of cisplatin with different nucleophiles, predominantly those containing sulfur (38–43). Two of them include nucleophiles used in the present investigation, thiosulfate and methionine. In both studies, a mixture of cisplatin and its hydrated complexes was used. In the first paper, the reaction kinetics of a hydrolysis solution of cisplatin with the nucleophiles mesna, dimesna, and thiosulfate were examined (41). Thiosulfate was by far the most nucleophilic; the observed half-lives of MHC were less than 1 min at thiosulfate concentrations of 2.6 and 50 mM at pH 5.3 and 37°C (41). For comparison, a MHC half-life of 1.4 mins in a 2.0 mM thiosulfate solution was observed in the present study. At low pH, shorter half-lives are expected for MHC, since it has a pKa of 6.56 (44) and its reactivity increases with a higher degree of protonation (3). In the second paper, the reaction of cisplatin and its hydrated species with L-methionine was explored at an unspecified pH (40). In contrast to the D-methionine results that are presented here, the degradation rate with the hydrolysis solution was faster than with cisplatin, with as well as without chloride ions present (40). A possible explanation for these diverging results is that the incubations may have been conducted at a lower pH than in the present investigation.

Local administration of an agent to prevent cisplatin-induced hearing damage is an attractive approach from several aspects. First, the risk of interaction with cisplatin at the tumor, leading to a reduced antitumoral effect, is minimized. Second, systemic toxic effects of the protector are avoided. Third, it is possible to achieve a higher local concentration of an otoprotectant in the inner ear compartments by a direct delivery via the round window membrane (45). Studies have confirmed that thiosulfate, methionine, and N-acetyl-L-cysteine may protect against cisplatin-associated hearing damage when applied locally to experimental animals (12, 17, 19, 46). 1,3-Dimethyl-2-thiourea has been shown to have otoprotective properties against ischemia-induced cochlear dysfunction when it has been administered locally to guinea pigs (47, 48). L-Cysteine methyl ester is a dark horse that was used in the present investigation because of its more lipophilic character (Fig. 1dGo), which might influence its uptake to the inner ear when administered to the middle ear. The data in Table 1Go imply that L-cysteine methyl ester may effectively inactivate cisplatin and, to an even greater extent, MHC.

Thus, nucleophilicity is only one of several factors that might influence the otoprotective effects of an agent. N-acetyl-L-cysteine was by far the weakest nucleophile (Table 1Go), but in vivo experiments have revealed that it is able to reduce the ototoxic effects of cisplatin (17). The degradation of MHC with D-methionine was more than 50 times slower than with thiosulfate (Table 1Go). However, in vivo, round window application of D-methionine was shown to protect against hearing damage, whereas thiosulfate did not (19). Although the molar amount of D-methionine was about four times higher than that of thiosulfate and, as shown here, the degradation rate of cisplatin and MHC depends strongly on the nucleophile concentration, it is more likely that the different results were caused by the fact that D-methionine, as being more lipophilic, more easily passes the round window membrane than does thiosulfate.

The molecular structure of the reaction products between cisplatin/MHC and the sulfur-containing compounds depends on the time of incubation as well as on the concentration of the reactants (40, 49, 50). The fact that most of the nucleophiles have demonstrated otoprotective properties in vitro (51) and in vivo (7, 8, 10, 11, 17, 19, 46) strongly suggests that the molecules formed are less toxic than cisplatin and MHC. Nonetheless, a few renal studies have shown that N-acetyl-L-cysteine and methionine may, in some cases, exacerbate the nephrotoxicity of cisplatin (28, 50, 52).

The inner ear is divided into two extracellular compartments filled with either perilymph or endolymph. The composition of the perilymph resembles that of plasma ultrafiltrate, whereas the endolymph has a unique composition defined by high potassium, high chloride, and low sodium contents (53). After administration to the middle ear for uptake to the inner ear, the otoprotectant is expected first to be distributed to the perilymph (18, 54). Cisplatin has been detected in the perilymph of guinea pigs a few minutes to 1 hr after having been injected intraveneously (55). The existence of MHC in the inner ear fluids remains to be established. However, considering the composition of the inner ear fluids, their pH being similar to that of plasma (53), and the fact that MHC has been detected in blood of cisplatin-treated patients (2), it is rather likely that MHC is indeed present in the inner ear. Recently, it was shown that the ototoxicity of cisplatin may be influenced by local pH manipulation; otoprotection was achieved by application of alkaline PBS to the round window niche, whereas acidic PBS was found to be detrimental to the inner ear function (56). This indicates that MHC might be involved in the ototoxic side effects of cisplatin, since the reactivity of MHC is affected by the pH, whereas that of cisplatin is not (3).


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Isolated MHC was shown to be significantly more reactive than cisplatin in the presence of the sulfur-containing nucleophiles L-cysteine methyl ester, 1,3-dimethyl-2-thiourea, and thiosulfate. Our results suggest that thiosulfate as being the strongest nucleophile is a promising agent for local otoprotective administration. However, it remains to be established how important rapid complexation of MHC and cisplatin is for preventing inner ear damage.


   Footnotes
 
This research was supported by Apoteket AB.

Received for publication January 2, 2006. Accepted for publication April 20, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. Reedijk J. New clues for platinum antitumor chemistry: kinetically controlled metal binding to DNA. Proc Natl Acad Sci U S A 100:3611–3616, 2003.[Abstract/Free Full Text]
  2. Andersson A, Fagerberg J, Lewensohn R, Ehrsson H. Pharmacokinetics of cisplatin and its monohydrated complex in humans. J Pharm Sci 85: 824–827, 1996.[Medline]
  3. Lempers ELM, Reedijk J. Interactions of platinum amine compounds with sulfur-containing biomolecules and DNA fragments. Adv Inorg Chem 37:175–217, 1991.
  4. Mandic A, Hansson J, Linder S, Shoshan MC. Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. J Biol Chem 278:9100–9106, 2003.[Abstract/Free Full Text]
  5. Gilmer Knight KR, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol 23:8588–8596, 2005.[Abstract/Free Full Text]
  6. Masuda H, Tanaka T, Takahama U. Cisplatin generates superoxide anion by interaction with DNA in a cell-free system. Biochem Biophys Res Commun 203:1175–1180, 1994.[Medline]
  7. Dickey DT, Muldoon LL, Kraemer DF, Neuwelt EA. Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model. Hear Res 193:25–30, 2004.[Medline]
  8. Dickey DT, Wu YJ, Muldoon LL, Neuwelt EA. Protection against cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels. J Pharmacol Exp Ther 314:1052–1058, 2005.[Abstract/Free Full Text]
  9. Ramesh G, Reeves WB. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Renal Physiol 289: F166–F174, 2005.[Abstract/Free Full Text]
  10. Campbell KCM, Rybak LP, Meech RP, Hughes L. D-Methionine provides excellent protection from cisplatin ototoxicity in the rat. Hear Res 102:90–98, 1996.[Medline]
  11. Reser D, Rho M, Dewan D, Herbst L, Li G, Stupak H, Zur K, Romaine J, Frenz D, Goldbloom L, Kopke R, Arezzo J, Van De Water T. L- and D-methionine provide equivalent long term protection against CDDP-induced ototoxicity in vivo, with partial in vitro and in vivo retention of antineoplastic activity. Neurotoxicology 20:731–748, 1999.[Medline]
  12. Li G, Frenz DA, Brahmblatt S, Feghali JG, Ruben RJ, Berggren D, Arezzo J, Van De Water TR. Round window membrane delivery of L-methionine provides protection from cisplatin ototoxicity without compromising chemotherapeutic efficacy. Neurotoxicology 22:163–176, 2001.[Medline]
  13. Howell SB, Taetle R. Effect of sodium thiosulfate on cis-dichlorodiammineplatinum(II) toxicity and antitumor activity in L1210 leukemia. Cancer Treat Rep 64:611–616, 1980.[Medline]
  14. Iwamoto Y, Kawano T, Ishizawa M, Aoki K, Kuroiwa T, Baba T. Inactivation of cis-diamminedichloroplatinum (II) in blood and protection of its toxicity by sodium thiosulfate in rabbits. Cancer Chemother Pharmacol 15:228–232, 1985.[Medline]
  15. Goel R, Cleary SM, Horton C, Kirmani S, Abramson I, Kelly C, Howell SB. Effect of sodium thiosulfate on the pharmacokinetics and toxicity of cisplatin. J Natl Cancer Inst 81:1552–1560, 1989.[Abstract/Free Full Text]
  16. Ekborn A, Laurell G, Johnstrom P, Wallin I, Eksborg S, Ehrsson H. D-Methionine and cisplatin ototoxicity in the guinea pig: D-methionine influences cisplatin pharmacokinetics. Hear Res 165:53–61, 2002.[Medline]
  17. Choe WT, Chinosornvatana N, Chang KW. Prevention of cisplatin ototoxicity using transtympanic N-acetylcysteine and lactate. Otol Neurotol 25:910–915, 2004.[Medline]
  18. Laurell G, Teixeira M, Sterkers O, Bagger-Sjoback D, Eksborg S, Lidman O, Ferrary E. Local administration of antioxidants to the inner ear. Kinetics and distribution. Hear Res 173:198–209, 2002.[Medline]
  19. Wimmer C, Mees K, Stumpf P, Welsch U, Reichel O, Suckfull M. Round window application of D-methionine, sodium thiosulfate, brain-derived neurotrophic factor, and fibroblast growth factor-2 in cisplatin-induced ototoxicity. Otol Neurotol 25:33–40, 2004.[Medline]
  20. Ehrsson HC, Wallin IB, Andersson AS, Edlund PO. Cisplatin, transplatin, and their hydrated complexes: separation and identification using porous graphitic carbon and electrospray ionization mass spectrometry. Anal Chem 67:3608–3611, 1995.
  21. Lim MC, Martin RB. The nature of cis amine Pd(II) and antitumor cis amine Pt(II) complexes in aqueous solutions. J Inorg Nucl Chem 38: 1911–1914, 1976.
  22. Ehrsson H, Wallin I. Liquid chromatographic determination of oxaliplatin in blood using post-column derivatization in a microwave field followed by photometric detection. J Chromatogr B 795:291–294, 2003.
  23. Andersson A, Ehrsson H. Determination of cisplatin and cis-diammineaquachloroplatinum(II) ion by liquid chromatography using post-column derivatization with diethyldithiocarbamate. J Chromatogr B 652:203–210, 1994.
  24. Elferink F, van der Vijgh WJF, Klein I, Pinedo HM. Interaction of cisplatin and carboplatin with sodium thiosulfate: reaction rates and protein binding. Clin Chem 32:641–645, 1986.[Abstract/Free Full Text]
  25. Nagai N, Okuda R, Kinoshita M, Ogata H. Decomposition kinetics of cisplatin in human biological fluids. J Pharm Pharmacol 48:918–924, 1996.[Medline]
  26. Dedon PC, Borch RF. Characterization of the reactions of platinum antitumor agents with biologic and nonbiologic sulfur-containing nucleophiles. Biochem Pharmacol 36:1955–1964, 1987.[Medline]
  27. Miller SE, House DA. The hydrolysis products of cis-dichlorodiammineplatinum(II) 3. Hydrolysis kinetics at physiological pH. Inorg Chim Acta 173:53–60, 1990.
  28. Daley-Yates PT, McBrien DCH. The inhibition of renal ATPase by cisplatin and some biotransformation products. Chem Biol Interact 40: 325–334, 1982.[Medline]
  29. Hannemann J, Duwe J, Baumann K. Iron- and ascorbic acid-induced lipid peroxidation in renal microsomes isolated from rats treated with platinum compounds. Cancer Chemother Pharmacol 28:427–433, 1991.[Medline]
  30. Kohl HH, Friedman ME, Melius P, Mora EC, McAuliffe CA. Enhanced inhibition of both cellular protein synthesis and malate dehydrogenase by aged aquoplatinum(II) complexes. Chem Biol Interact 24:209–215, 1979.[Medline]
  31. Yachnin JR, Wallin I, Lewensohn R, Sirzen F, Ehrsson H. The kinetics and cytotoxicity of cisplatin and its monohydrated complex. Cancer Lett 132:175–180, 1998.[Medline]
  32. Zheng H, Fink D, Howell SB. Pharmacological basis for a novel therapeutic strategy based on the use of aquated cisplatin. Clin Cancer Res 3:1157–1165, 1997.[Abstract]
  33. Jones MM, Basinger MA, Beaty JA, Holscher MA. The relative nephrotoxicity of cisplatin, cis-[Pt(NH3)2(guanosine)2]2+, and the hydrolysis product of cisplatin in the rat. Cancer Chemother Pharmacol 29:29–32, 1991.[Medline]
  34. Ekborn A, Lindberg A, Laurell G, Wallin I, Eksborg S, Ehrsson H. Ototoxicity, nephrotoxicity and pharmacokinetics of cisplatin and its monohydrated complex in the guinea pig. Cancer Chemother Pharmacol 51:36–42, 2003.[Medline]
  35. Daley-Yates PT, McBrien DCH. Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumour activity of cisplatin. Biochem Pharmacol 33:3063–3070, 1984.[Medline]
  36. Bancroft DP, Lepre CA, Lippard SJ. 195Pt NMR kinetic and mechanistic studies of cis- and trans-diamminedichloroplatinum(II) binding to DNA. J Am Chem Soc 112:6860–6871, 1990.
  37. Segal E, Le Pecq JB. Role of ligand exchange processes in the reaction kinetics of the antitumor drug cis-diamminedichloroplatinum(II) with its targets. Cancer Res 45:492–498, 1985.[Abstract/Free Full Text]
  38. Corden BJ. Reaction of platinum(II) antitumor agents with sulfhydral compounds and the implications for nephrotoxicity. Inorg Chim Acta 137:125–130, 1987.
  39. Dabrowiak JC, Goodisman J, Souid AK. Kinetic study of the reaction of cisplatin with thiols. Drug Metab Dispos 30:1378–1384, 2002.[Abstract/Free Full Text]
  40. Heudi O, Cailleux A, Allain P. Kinetic studies of the reactivity between cisplatin and its monoaquo species with L-methionine. J Inorg Biochem 71:61–69, 1998.
  41. Leeuwenkamp OR, Neijt JP, van der Vijgh WJF, Pinedo HM. Reaction kinetics of cisplatin and its monoaquated species with the modulating agents (di)mesna and thiosulphate. Eur J Cancer 27:1243–1247, 1991.[Medline]
  42. Miller SE, House DA. The hydrolysis products of cis-diamminedi-chloroplatinum(II) 5. The anation kinetics of cis-Pt(X)(NH3)2(OH2)+(X=Cl, OH) with glycine, monohydrogen malonate and chloride. Inorg Chim Acta 187:125–132, 1991.
  43. Ohta N, Inagaki K, Muta H, Yotsuyanagi T, Matsuo T. Reaction of oxidized glutathione with cis- and trans-diamminedichloroplatinum(II) and their aquated complexes through the disulfide bond. Int J Pharm 161:15–21, 1998.
  44. Andersson A, Hedenmalm H, Elfsson B, Ehrsson H. Determination of the acid dissociation constant for cis-diammineaquachloroplatinum(II) ion. A hydrolysis product of cisplatin. J Pharm Sci 83:859–862, 1994.[Medline]
  45. Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids: an animal study followed by clinical application. Laryngoscope 109:1–17, 1999.[Medline]
  46. Wang J, Lloyd Faulconbridge RV, Fetoni A, Guitton MJ, Pujol R, Puel JL. Local application of sodium thiosulfate prevents cisplatin-induced hearing loss in the guinea pig. Neuropharmacology 45:380–393, 2003.[Medline]
  47. Tabuchi K, Tsuji S, Fujihira K, Oikawa K, Hara A, Kusakari J. Outer hair cells functionally and structurally deteriorate during reperfusion. Hear Res 173:153–163, 2002.[Medline]
  48. Tabuchi K, Tsuji S, Ito Z, Hara A, Kusakari J. Does xanthine oxidase contribute to the hydroxyl radical generation in ischemia and reperfusion of the cochlea? Hear Res 153:1–6, 2001.[Medline]
  49. El-Khateeb M, Appleton TG, Gahan LR, Charles BG, Berners-Price SJ, Bolton AM. Reactions of cisplatin hydrolytes with methionine, cysteine, and plasma ultrafiltrate studied by a combination of HPLC and NMR techniques. J Inorg Biochem 77:13–21, 1999.[Medline]
  50. Townsend DM, Marto JA, Deng M, Macdonald TJ, Hanigan MH. High pressure liquid chromatography and mass spectrometry characterization of the nephrotoxic biotransformation products of cisplatin. Drug Metab Dispos 31:705–713, 2003.[Abstract/Free Full Text]
  51. Feghali JG, Liu W, Van De Water TR. L-N-acetyl-cysteine protection against cisplatin-induced auditory neuronal and hair cell toxicity. Laryngoscope 111:1147–1155, 2001.[Medline]
  52. Alden WW, Repta AJ. Exacerbation of cisplatin-induced nephrotoxicity by methionine. Chem Biol Interact 48:121–124, 1984.[Medline]
  53. Sterkers O, Saumon G, Tran Ba Huy P, Ferrary E, Amiel C. Electrochemical heterogeneity of the cochlear endolymph: effect of acetazolamide. Am J Physiol 246:F47–F53, 1984.
  54. Salt AN, Ma Y. Quantification of solute entry into cochlear perilymph through the round window membrane. Hear Res 154:88–97, 2001.[Medline]
  55. Laurell G, Andersson A, Engstrom B, Ehrsson H. Distribution of cisplatin in perilymph and cerebrospinal fluid after intravenous administration in the guinea pig. Cancer Chemother Pharmacol 36: 83–86, 1995.[Medline]
  56. Tanaka F, Whitworth CA, Rybak LP. Round window pH manipulation alters the ototoxicity of systemic cisplatin. Hear Res 187:44–50, 2004.[Medline]



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V. Hellberg, I. Wallin, S. Eriksson, E. Hernlund, E. Jerremalm, M. Berndtsson, S. Eksborg, E. S. J. Arner, M. Shoshan, H. Ehrsson, et al.
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